Role of adolescent stress in the acceleration of Alzheimer's disease related-cognitive impairment

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PROJECT SUMMARY/ABSTRACT The primary goal of our NIMH R01 project (R01MH116869) is to elucidate the role of adolescent stress on social cognition in the postpartum period. We have discovered that adolescent psychosocial stress, in conjunction with the stressful events of pregnancy/delivery, leads to long-lasting deficits in social behaviors in the postpartum period. We have also demonstrated that the social behavioral deficits in stressed dams are caused by glucocorticoid receptor (GR)-mediated functional alteration of anterior insula (AI)-prelimbic cortex (PrL) projections. These results show the causal role of enhanced GR signaling in the AI-PrL pathway underlying adolescent stress-induced social behavioral deficits in the postpartum period. Recent studies demonstrate that females have a significantly greater risk for the development of Alzheimer’s disease (AD) than males. Early life stress drives the progression of AD and exacerbates symptoms. Pathology in AI and dorsal anterior cingulate cortex [dACC, homologous to the PrL in rodents] have been implicated in AD. However, the mechanisms underlying the deficits at the circuit level remain unclear. By modifying the protocol of our ongoing R01 project, we may be able to explore the relationship between the dysfunction of this circuit and the acceleration of the AD-related phenotypes in females. In this proposed supplemental study, we will test the hypothesis that adolescent social isolation, in conjunction with the stressful events of pregnancy/delivery, accelerates the onset of AD-related deficits in social behaviors via AI-PrL functional alterations. To address our hypothesis, we will pursue the following specific two Aims: In Aim 1, we will examine whether adolescent social isolation accelerates the onset of AD-related deficits in social behaviors in 5xFAD dams. Plasma corticosterone levels, plaques of Aβ and amyloid, and synaptic density will be measured to examine the effects of adolescent stress on regulation of the HPA axis and AD-related neuropathology in 5xFAD dams. In Aim 2, we will investigate how mediation of the AI-PrL projections, a novel cortico-cortical pathway, alters social behaviors in 5xFAD dams exposed to adolescent social isolation. This supplemental study will generate critical data to understand the influence of adolescent psychosocial stress on neuronal function and behavior in the context of AD. The finding will also stimulate research to manipulate a specific circuit at a critical period in order to intervene in AD-related pathology and symptoms.